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BIOC 400:

IMMUNOLOGY (30/30 HRS CF:3
...

NB: Only when the external barriers are breached will the innate and adaptive
mechanisms be activated
...




The flow of urine, tears and peristalsis (distinctive pattern of smooth muscle
contractions) reduces contact time between the pathogen and cells, limiting
the attachment of microbial surface molecules and thus providing a further
protective mechanism The barrier effect of mucosal membranes is more
limited than for skin because these may only be one cell thick, in such
situations, additional protective mechanisms have developed; including, for
example, the secretion in the pulmonary alveoli of surfactant proteins which
can act as bacterial opsonin
...

Additionally, on the skin and in the vagina, they contribute to the low pH (
5
...
Lactic acid secreted by sweat glands helps
maintain the low skin Ph
...




Finally, there are secreted antimicrobial molecules, including antibacterial
peptides (defensins) and the enzyme lysozyme (present in saliva), which are
produced as a result of innate mechanisms and operate at the external barrier
level
...

The recognition function is based on identifying specific microbial molecules and
the elimination function on phagocytosis and the activation of various plasma
proteins
...

The innate recognition function requires sentry cells, mainly immature dendritic
cells with assistance from tissue-based macrophages
...

PAMPs are invariant molecular constituents of infectious microorganisms that are
shared by a variety of pathogens, but not usually found in the host
...

PRRs are located on or within cells and in plasma/tissue fluids where they
function as recognition molecules for PAMPs
...


The complement protein C3 is a recognition molecule for foreign antigen
including bacterial LPS and viruses
...

The process of binding between the PRR and its specific PAMP initiates a series
of actions leading to microbe death
...

Complement consists of at least 20 plasma proteins that have both antigen
recognition and effector functions
...

 First, particular activated complement proteins are able to bind to the surface
of the microbe facilitating phagocytosis
...

Opsonization describes the mechanism whereby invading pathogens are coated
with either complement molecules (for example activated C3) or antibody (for
example IgG)
...

Host cells are protected from the destructive effects of the innate system by the
expression of gene encoded self-molecules on the surface of uninfected host
cells
...

There are two additional mechanisms that protect against many viral infections
...

Interferons are generally classified into two types, I and II
...

Type II interferons (synonym interferon- ) are secreted by natural killer (NK) cells
and T cells and activate NK cells, T cells, endothelial cells and macrophages
...

Virus-infected cells may express viral proteins on the cell surface, these can be
recognized by multiple activatory receptors on NK cells which then kill the
infected cell using the same final pathway mechanisms as Tc cells, namely,
secretion of perforin and granzymes
...

Because of the potential damage induced by NK cell activation, NK cells express
a number of inhibitory receptors that bind to the MHC I molecules expressed by
normal host cells and prevent NK cell activation
...
It is an evolutionary response to those pathogens which
have developed the ability to evade host external and innate barriers and invade
tissues; such pathogen evasion strategies can involve
i
...

depletion of immune cells,
iii
...

mutation
...

The recognition function is based on receptors, either
cell surface (on T and B cells) or
circulating in plasma (antibodies), that identify specific molecular
sequences or conformational patterns on microbes
...

Tissue invading pathogens are either intracellular or extracellular replicating
microbes
...
The systems
are, however, highly integrated with a number of viruses (obligate intracellular
pathogens) being eliminated during their viraemic phase by neutralizing
antibodies
...
These are produced by B cells and are located on the cell surface or
secreted in serum, other extracellular fluids and on mucous membranes
...
Each B
cell has a unique receptor that recognizes the specific molecular sequence or
conformational pattern on a particular microbe
...
Each B cell will
express many thousands of copies of this unique BCR on its cell surface
...
Antigen recognition takes place here,
a
...
lymph nodes in the case of microbes that enter through the skin and
mucous membranes and
c
...
Antigen binding to the BCR will subsequently result in B-cell
activation, proliferation and differentiation
...

 pathogens replicate within the phagosome (for example Mycobacteria)
...

Cytosolic pathogens include most viruses and some bacteria (for example
Listeria)
...
Viral genetic material is released and transcription occurs
leading to the production of viral proteins, which are then assembled into new
virions
...
Tc cells, each with a unique TCR,
constantly circulate throughout the body sampling the cell surfaces looking for
signs of infection; binding of the TCR with the MHC I (containing the viral
fragment) activates the Tc cell which releases (by exocytosis) cytokines
(including perforin and granzymes) that cause the infected cell to undergo
apoptosis
...

TH1 cells recognize antigen through MHC II: microbial antigen complexes
expressed by infected macrophages
...
g
...
A common feature of both these infections is
the secretion of either IL-12 during the innate immune response or IFN- by NK
cells (causing macrophages to secrete IL-12)
...
It should be
noted that a subset of TH1 cells can also activate B cells leading to the
development of antibody-secreting and memory B cells
...
As the
microorganism is eliminated and antigen correspondingly declines, the majority
(>95%) of effector cells are removed by apoptosis
...
Besides this, some diseases are themselves
caused due to hyperactivity of immune system, with T-lymphocytes playing the
ultimate role
...

The cytotoxic activity of cytotoxic T-cells is caused by either of the 2 pathways:
Perforin Pathway- The activated cytotoxic T-cells release perforins which
punches holes in the cell membrane of target cell, resulting in its lysis and hence
death
...


ANTIGENS
An antigen is a molecule recognized by the immune system
...
Autoimmune disorders arise from the
immune system reacting to its own antigens
...
There is a slight difference
between an immunogen and antigen
...

Immunogenicity is the ability to induce a humoral and/or cell-mediated immune
response
Antigenicity is the ability to combine specifically with the final products of the
[immune response] (i
...
secreted antibodies and/or surface receptors on T-cells)
...

Antigens are usually proteins or polysaccharides
...
Lipids and nucleic acids are antigenic only when combined with
proteins and polysaccharides
...
Vaccines are examples of immunogenic
antigens intentionally administered to induce acquired immunity in the recipient
...
Exogenous antigens
2
...
Autoantigens
4
...
Native antigens
Exogenous antigens
Exogenous antigens are antigens that have entered the body from the outside,
for example by inhalation, ingestion, or injection
...
The exogenous
antigens are taken into the antigen-presenting cells (APCs) and processed into
fragments
...
Cytokines can activate cytotoxic T lymphocytes (CTL),
antibody-secreting B cells, macrophages, and other particles
...
Intracellular antigens can be released back
into circulation upon the destruction of the infected cell, again
...

The fragments are then presented on the cell surface in the complex with MHC
class I molecules
...

Endogenous antigens include xenogenic (heterologous), autologous and
allogenic (homologous) antigens
...
These antigens should, under
normal conditions, not be the target of the immune system, but, due to mainly
genetic and environmental factors, the normal immunological tolerance for such
an antigen has been lost in these patients
...
These antigens
can sometimes be presented by tumor cells and never by the normal ones
...
More common are antigens that are presented by
tumor cells and normal cells, and they are called tumor-associated antigens
(TAAs)
...

Tumor antigens can also be on the surface of the tumor in the form of, for
example, a mutated receptor, in which case they will be recognized by B cells
...
Oncofetal: typically only expressed in fetal tissues and in cancerous somatic
cells
2
...
Overexpressed/ accumulated: expressed by both normal and neoplastic
tissue, with the level of expression highly elevated in neoplasia
4
...
Lineage-restricted: expressed largely by a single cancer histotype
6
...
Posttranslationally altered: tumor-associated alterations in glycosylation,
etc
...
Idiotypic: highly polymorphic genes where a tumor cell expresses a specific
“clonotype”, ie, as in B cell, T cell lymphoma/leukemia resulting from clonal
aberrancies
...
T cells cannot bind native antigens, but require that they be processed by
APCs, whereas B cells can be activated by native ones
...

General functions of immunoglobulins
A
...
Each
immunoglobulin actually binds to a specific antigenic determinant
...
The valency of antibody refers to the number of antigenic
determinants that an individual antibody molecule can bind
...

B
...

Rather, the significant biological effects are a consequence of secondary
"effector functions" of antibodies
...
Usually the ability to carry out a particular effector
function requires that the antibody bind to its antigen
...
Such effector functions include:
1
...

2
...
This binding can
activate the cells to perform some function
...
As a result, the transferred maternal
antibodies provide immunity to the fetus and newborn
Basic structure of immunoglobulins
Although different immunoglobulins can differ structurally, they all are built from
the same basic units
...
Heavy and Light Chains
All immunoglobulins have a four chain structure as their basic unit
...
Disulfide bonds
1
...
The number of inter-chain disulfide bonds varies among different
immunoglobulin molecules
...
Intra-chain disulfide binds - Within each of the polypeptide chains there are
also intra-chain disulfide bonds
...
Variable (V) and Constant (C) Regions
When the amino acid sequences of many different heavy chains and light chains
were compared, it became clear that both the heavy and light chain could be
divided into two regions based on variability in the amino acid sequences
...
Light Chain - VL (110 amino acids) and CL (110 amino acids)
2
...
Hinge Region
This is the region at which the arms of the antibody molecule form a Y
...

E
...
Rather, it is folded into globular regions
each of which contains an intra-chain disulfide bond
...

1
...
Heavy Chain Domains - VH, CH1 - CH3 (or CH4)
F
...

However, in some cases carbohydrates may also be attached at other locations
...


A
...
This results in the
formation of two identical fragments that contain the light chain and the VH and
CH1 domains of the heavy chain
...
Each Fab fragment is

monovalent whereas the original molecule was divalent
...
An antibody is able to bind a
particular antigenic determinant because it has a particular combination of VH
and VL
...

B
...
This fragment
was called Fc because it was easily crystallized
...
Different functions are mediated by the different
domains in this fragment, figure below
...

C
...
This fragment was called F(ab')2 because it
is divalent
...
The Fc region of the molecule is digested into small
peptides by pepsin

Human immunoglobulin classes, subclasses, types and subtypes
A
...
All immunoglobulins within a given class will have very similar heavy
chain constant regions
...
e
...

1
...
IgM - Mu heavy chains
3
...
IgD - Delta heavy chains
5
...
Immunoglobulin Subclasses
The classes of immunoglobulins can be divided into subclasses based on small
differences in the amino acid sequences in the constant region of the heavy
chains
...
Again these differences are most
commonly detected by serological means
...
IgG Subclasses
a) IgG1 - Gamma 1 heavy chains

b) IgG2 - Gamma 2 heavy chains
c) IgG3 - Gamma 3 heavy chains
d) IgG4 - Gamma 4 heavy chains
Structure and some properties of IgG class and subclasses
 Structure
All IgG's are monomers (7S immunoglobulin)
...
The structures of the
IgG subclasses are presented below:

 Properties
IgG is the most versatile immunoglobulin because it is capable of carrying out all
of the functions of immunoglobulin molecules
...

Transfer is mediated by a receptor on placental cells for the Fc region of IgG
...

d) Fixes complement - Not all subclasses fix equally well; IgG4 does not fix
complement

e) Binding to cells - Macrophages, monocytes, PMNs and some lymphocytes
have Fc receptors for the Fc region of IgG
...
A consequence of binding to the Fc
receptors on PMNs, monocytes and macrophages is that the cell can now
internalize the antigen better
...
The term opsonin is used to describe substances that
enhance phagocytosis
...
Binding of IgG to Fc receptors on
other types of cells results in the activation of other functions
...
IgM
Structure and some properties of IgM class
The structure of IgM is presented in the figure below
...
In the
pentameric form all heavy chains are identical and all light chains are identical
...
IgM has an extra domain on the mu chain
(CH4) and it has another protein covalently bound via a S-S bond called the J
chain
...




Properties

a) IgM is the third most common serum Ig
...


c) As a consequence of its pentameric structure, IgM is a good complement
fixing Ig
...

d) As a consequence of its structure, IgM is also a good agglutinating Ig
...

e) IgM binds to some cells via Fc receptors
...


Cell surface IgM functions as a receptor for antigen on B cells
...
These additional proteins act as signal
transducing molecules since the cytoplasmic tail of the Ig molecule itself is too
short to transduce a signal
...
In the case of T-independent antigens, contact between the antigen and
surface immunoglobulin is sufficient to activate B cells to differentiate into
antibody secreting plasma cells
...


3
...
When IgA exits as a dimer, a J chain is associated with it
...
Unlike the remainder of the IgA which is made in the plasma
cell, the secretory piece is made in epithelial cells and is added to the IgA as it
passes into the secretions
...



Properties

a) IgA is the 2nd most common serum Ig
...

Since it is found in secretions secretory IgA is important in local (mucosal)
immunity
...

d) IgA can binding to some cells - PMN's and some lymphocytes
...
IgD
Structure and some properties of IgD class
 Structure
IgD exists only as a monomer
...

b) IgD is primarily found on B cell surfaces where it functions as a receptor for
antigen
...
It also associates with the Ig-alpha and Ig-beta
chains
...

5
...




Properties

a) IgE is the least common serum Ig since it binds very tightly to Fc receptors on
basophils and mast cells even before interacting with antigen
...
Binding of the allergen to the IgE
on the cells results in the release of various pharmacological mediators that
result in allergic symptoms
...
Since serum IgE levels
rise in parasitic diseases, measuring IgE levels is helpful in diagnosing parasitic
infections
...

d) IgE does not fix complement
...
Immunoglobulin Types
Immunoglobulins can also be classified by the type of light chain that they have
...
These differences are detected by serological
means
...
Kappa light chains
2
...
Immunoglobulin Subtypes
The light chains can also be divided into subtypes based on differences in the
amino acid sequences in the constant region of the light chain
...
Lambda subtypes
a) Lambda 1
b) Lambda 2
c) Lambda 3
d) Lambda 4

E
...
In addition,
different immunoglobulin molecules can have different antigen binding properties
because of different VH and VL regions
...

The complement system consists of a number of small proteins found in the
blood, generally synthesized by the liver, and normally circulating as inactive
precursors (pro-proteins)
...
The end-result of this activation
cascade is massive amplification of the response and activation of the cell-killing
membrane attack complex
...
These
proteins are synthesized mainly in the liver, and they account for about 5% of the
globulin fraction of blood serum
...
g
...
) but
some are simply refered to as "Factors"
...


Components of the Classical Pathway
Native
component

Cleaves C1s to activate protease function
...


C2a

Unknown
...

Mediates inflammation; anaphylatoxin
...

Binds cell surfaces for opsonization and activation of
alternate pathway
...


C1s
C2

Function(s)

C1q
C1(q,r,s)

Active
component(s)

Mediates inflammation
...
Binds cell surfaces for
opsonization
...


C3b

Binds cell surfaces for opsonization and activation of
alternate pathway
...
Cleaved by Factor D
...


Bb

Cleaved form stabilized by P produces C3 convertase
...


Properdin

P

Binds and stabilizes membrane bound C3bBb
...


C5b

Initiates assembly of the membrane-attack complex
(MAC)
...


C7

C7

Binds C5b6, inserts into membrane, forms acceptor for
C8
...


C9

C9n

Polymerizes around C5b678 to form channel that causes
cell lysis
...
C1q is the actual recognition portion
...
C2b and C4b combine
to produce C3 convertase (C3 activating enzyme)
...

C3 is central to both the classical and alternative pathways
...
C3a is a potent anaphylatoxin
...
C3b can also bind
directly to cells making them susceptible to phagocytosis
...
e
...
C5a has potent
anaphylatoxic and chemotaxic activities
...

MAC includes C5b, C6, C7, C8 and C9
...

Schematic presentation of Classical Pathway

Component
cleavage
Enzymatic activity
Component
assembly



The Alternate Complement Pathway

The alternate pathway may be initiated by immunologic (e
...
IgA or IgE) or nonimmunologic (e
...
LPS) means
...
A small amount of
C3b is always found in circulation as a result of spontaneous cleavage of C3 but
the concentrations are generally kept very low
...
Then Factor B
binds to C3b
...
Next
...
Finally, a C3bBb3b complex forms and this is a C5 convertase, cleaving C5
to C5a/b
...


Schematic representation of Alternate Pathway

Component cleavage
Enzymatic activity
Component assembly
Generally, only Gram-negative cells can be directly lysed by antibody plus
complement; Gram-positive cells are mostly resistant
...
In addition, complement can
neutralize virus particles either by direct lysis or by preventing viral penetration of
host cells
...
This pathway is
activated by binding mannose-binding lectin to mannose residues on the
pathogen surface, which activates the MBL-associated serine proteases, MASP1, and MASP-2 (very similar to C1r and C1s, respectively), which can then split
C4 into C4a and C4b and C2 into C2a and C2b
...
Ficolins are homologous
to MBL and function via MASP in a similar way
...

Regulation of the complement cascade
The complement system has the potential to be extremely damaging to host
tissues, meaning its activation must be tightly regulated
...

 C1 Inhibitor inhibits the production of C3b by combining with and inactivating
C1r and C1s
...

 Protein H inhibits the production of C3b by inhibiting the binding of Factor B to
membrane-bound C3b, thereby preventing cleavage of B to Bb and
production of the C3 convertase, C3bBb
...
Factor I only works on cell membrane bound C3b, mostly
on red blood cells (i
...
non-activator surfaces)
...


CELLS OF THE IMMUNE SYSTEM
All cells of the immune system originate from a hematopoietic stem cell in the
bone marrow, which gives rise to two major lineages, a myeloid progenitor cell
and a lymphoid progenitor cell (Figure below)
...
Theses cells make up the cellular components of the innate
(non-specific) and adaptive (specific) immune systems
...
Cells of the innate immune system-NeM Natural Killer cells BED
...
The receptors of these cells are
pattern recognition receptors (PRRs) that recognize broad molecular patterns
found on pathogens (pathogen associated molecular patterns, PAMPS)
...
They phagocytose invading organisms (e
...

bacteria) and other foreign cells and kill them intracellularly
...

Neutrophils circulate in the bloodstream and must be signaled to leave the
bloodstream and enter tissues
...

Neutrophils also release substances that produce fibers in the surrounding
tissue
...
In addition, PMNs contribute to collateral
tissue damage that occurs during inflammation
...


Monocytes move to the tissues when infection occurs
...
The granules are filled with enzymes
and other substances that help kill and digest bacteria and other foreign cells
...
Furthermore, macrophages contribute to tissue repair
and act as antigen-presenting cells, which are required for the induction of
specific immune responses
...
Natural killer cells attach to foreign cells and
release enzymes and other substances that damage the outer membranes of
the foreign cells
...
Thus, natural killer cells are important in the
initial defense against viral infections
...

Also, natural killer cells produce cytokines that regulate some of the
functions of T cells, B cells, and macrophages
...
They contain granules that release
enzymes and other toxic substances when foreign cells are encountered
...
They are
however, less active against bacteria than are neutrophils and macrophages
...

Eosinophils help destroy cancer cells
...
People
with allergies, parasitic infections, or asthma often have more eosinophils
in the bloodstream than people without these disorders
...
They contain granules filled with
histamine, a substance involved in allergic reactions
...
Histamine increases blood flow to damaged tissues
...




Dendritic cells reside in the skin, lymph nodes, and tissues throughout
the body
...
Dendritic cells present antigen fragments to T cells in the lymph
nodes
...

B
...
These cells include dendritic cells and
macrophages
...
B lymphocytes also express class II MHC molecules
and they also function as APCs, although they are not considered as part of the
innate immune system
...
g
...

C
...
After exposure to antigen, B cells differentiate into plasma cells
whose primary function is the production of antibodies
...

B cells
B cells are lymphocytes that play a large role in the humoral immune response
...

B cells are an essential component of the adaptive immune system
...
Each B cell
has a unique receptor protein (referred to as the B cell receptor (BCR)) on its
surface that will bind to one particular antigen
...

Once a B cell encounters its cognate antigen and receives an additional signal
from a T helper cell, it can further differentiate into either plasma B cells or
memory B cells
...
These are short lived cells and undergo
apoptosis when the inciting agent that induced immune response is eliminated
...

Memory B cells are formed from activated B cells that are specific to the antigen
encountered during the primary immune response
...

B-1 cells express IgM in greater quantities than IgG and their receptors show
polyspecificity, meaning that they have low affinities for many different antigens,
but have a preference for other immunoglobulins, self antigens and common
bacterial polysaccharides
...

B cells activation
B cell recognition of antigen is not the only element necessary for B cell
activation (a combination of clonal proliferation and terminal differentiation into
plasma cells)
...

T cell-dependent activation
Once a pathogen is ingested by an antigen-presenting cell such as a
macrophage or dendritic cell, the pathogen's proteins are then digested to
peptides and attached to a class II MHC protein
...
The macrophage is now activated to deliver
multiple signals to a specific T cell that recognizes the peptide presented
...
Helper T cells (i
...
CD4+ T cells)
then activate specific B cells through a phenomenon known as an Immunological
synapse
...
e
...

Binding of the naive BCR with its specific antigen does not immediately result in
activation of the cell; rather it requires additional signals that are provided by a T
cells (TH2 cell), such antigens, which include proteins, are termed T-dependent
antigens
...
T dependent antigens contain proteins that are presented on B cell
Class II MHC to a special subtype of T cell called a Th2 cell
...
These cytokines trigger B cell
proliferation and differentiation into plasma cells which produce and secrete
initially IgM, and then isotype switching to IgG, IgA, and IgE
...
in addition, a subset of B cells differentiate to become longlived memory cells
...

Subsequent exposure to the microbe results in activation of the memory B cells
leading to more rapid production of antibody, often within 1-2 days

T cell-independent activation
Many antigens are T cell-independent in that they can deliver both of the signals
to the B cell
...
Many bacteria have
repeating carbohydrate epitopes that stimulate B cells, by cross-linking the IgM
antigen receptors in the B cell, responding with IgM synthesis in the absence of T
cell help
...
g
...
g
...

T Lymphocytes and their activation
T-Lymphocytes primarily compose of
 T-Helper,
 T-Cytotoxic and
 T-Suppressor Cells
...

1
...

T-helper cells consist of regular eukaryotic leukocyte cells; the difference being
primarily in the cell membrane molecules
...

CD4 – This is present only on T-helper cells and characterizes this sub-class of
lymphocytes
...

Th1 cells inhibit development of Th2 cells, while
Th2 cells inhibit Th1 cell development, macrophage activation and
bactericidal activity
...
These antigens may be bacterial antigen, xenobiotics (foreign substances)

etc
...

The APC have special components called Major Histocompatibility Complex- II
(MHC-II) which aid in their recognition by the lymphocytes
...

This plays as an initial actor to stimulate T-helper cells later in the play
...
The only task that is
remaining is to summon the T-Helper cells
...
These chemicals are chemo attractant in
nature and allure the lymphocytes
...
Usually, Th1 type helper cells are activated by this process
...
Subsequently, the
microbe is degraded and antigenic fragments are bound to MHC II molecules
which then migrate to the cell surface where they display the MHC II:antigen
complex
...
Identifying and then
binding of the MHC II:antigen complex to the specific T H2 receptor then activates
the naive T cell, causing it to proliferate
...

2
...
It has 2 main receptors:
TCR- T-Cell Receptor is common to both T-Helper cells and T-Cytotoxic cells
and functions to bind the MHC classes in the body and thereby getting evoked to
play a role lethal for microbial (and even body’s own cells, sometimes) cells
...

The initial Stimulus
The initial impulse depends much upon the antigens against which the body has
to act, as similarly shown for T-Helper cells
...
These peptides enter the eukaryotic cells
(host’s cells), enter the Rough Endoplasmic Reticulum and get processed to act
as an effective antigen
...
A second way of introduction of viral peptide is the
synthesis (by transcription and translation) of viral peptide itself by the viral DNA
and from there on similar cascade follows
...
The next task that
is performed is to summon the T-Cytotoxic cells
...
The T-Cytotoxic cells
approach the infected host cell as well as tumour cells and kill them after they
bind to them because they possess a TCR and CD8 which is specific for MHC-I
found over host cells
...

Cytokines have a short half-life, and they’re present in low concentrations
...
g
...

They regulate the intensity and duration of the inflammatory/immune response by
stimulating/inhibiting activation, proliferation and/or differentiation and migration
of multiple cell types and by regulating the synthesis and secretion of
immunoglobulins and other cytokines
...

Cytokines classification
Cytokines are classified depending either on their origin, such as lymphokines
(produced by lymphocytes), monokines (monocytes) or on their activity:
chemokines, interleukines, interferon
...
g
...
However, many are multifunctional molecules with
diverse biological actions and target cells
...
g
...

There is also duplication of function between cytokines; for example, IL-1 shares
activities with macrophage colony stimulating factor (M-CSF) on hemopoietic
cells, with IL-6 on the induction of acute-phase proteins, and with TNF and IL-6 in
inducing fever
...
Involved in the activation, maturation,
proliferation and inflammation of Th cells, B cells, NK cells; and activation of
other acute phase responses such as fever
...

Interleukin 3 (IL-3) produced by Th, mast and NK cells
...

Interleukin-4 (IL-4) produced by Th2 cell, B cells, macrophages, mast cells
and basophils
...
They also
participate in allergic and autoimmune reactions
...
They target
activated B cells, development, activation and chemoattraction of eosinophils
Interleukin-6 (IL-6) produced by monocytes, macrophages, Th2 cells and
stromal cells (connective tissue cells of an organ found in the loose
connective tissue)
...

Interleukin-7 (IL-7); produced by bone marrow stroma
...

Interleukin-8 (IL-8); produced by T cells, monocytes and neutrophils
...

Interleukin-10 (IL-10) produced by B and Th2 cells and macrophages
...

Interleukin-12 (IL-12) is produced by B cells, macrophages and dendritic cells
...

Interleukin-13 (IL-13) is produced by T cells and involved in the activation of B
cells, suppression of Th1 cells and increases epithelial mucus production
...

Interleukin-18 (IL-18) is produced by macrophages and induces INF-γ
production by T and NK cells
...
They are
involved in the differentiation of pluripotent stem cells, development of
neutrophils, eosinophils and macrophages
...
As a colony stimulating factor, it causes
development and activation of neutrophils
...
Involved in development and activation of
monocytes and macrophages
...
They have antiviral activity, stimulate macrophages
and NK cells and enhance HLA class I expression
...
Stimulate
macrophages and endothelium
...
It also enhances HLA
class I and II expression as well as suppressing Th2 cells
...
Activates macrophages granulocytes, cytotoxic cells
and endothelium
...
In addition, it has antitumor
effects
...
It has similar
functions to Tumor necrosis factor alpha (TNF-α)
...
Inhibits T and B cell proliferation and NK cell activity
...

The body naturally produces small amounts of these substances
...
This strategy involves giving
larger amounts of these substances by injection or infusion in the hope of
stimulating the cells of the immune system to act more effectively
...
It has also demonstrated therapeutic effectiveness against
hematologic diseases such as low-grade Hodgkin's lymphoma, cutaneous T-cell
lymphoma, multiple myeloma
...

BRM’s SIDE EFFECTS
The side effects of BRM therapy often include flu-like symptoms such as chills,
fever, muscle aches, weakness, loss of appetite, nausea, vomiting, and diarrhea
...
Interleukin
therapy can cause swelling
...


HYPESENSITIVITY
Hypersensitivity refers to excessive, undesirable (damaging, discomfortproducing and sometimes fatal) reactions produced by the normal immune
system
...

Hypersensitivity reactions can be divided into four types: type I, type II, type III
and type IV, based on the
 mechanisms involved and
 time taken for the reaction
...

Exposure may be by
 ingestion,
 inhalation,
 injection, or
 direct contact
...
This class
of antibodies binds to Fc receptors on the surface of tissue mast cells and blood
basophils
...
Later
exposure to the same allergen, cross-links the bound IgE on sensitized cells
resulting in degranulation (release of granules) and the secretion of
pharmacologically active mediators such as histamine, leukotriene (LTC4 and
LTD4), and prostaglandin that act on the surrounding tissues
...

Treatment usually involves administration of epinephrine, antihistamines, and
corticosteroids
...
The
antigens recognized in this way may either be intrinsic ("self" antigen, innately
part of the patient's cells) or extrinsic (absorbed onto the cells during exposure to
some foreign antigen, possibly as part of infection with a pathogen)
...


An example here is the reaction to penicillin where the drug can bind to red blood
cells causing them to be recognised as different, B cell proliferation will take
place and antibodies to the drug are produced
...
That is, mediators of acute inflammation
are generated at the site and membrane attack complexes cause cell lysis and
death
...

Another form of type II hypersensitivity is called antibody-dependent cellmediated cytotoxicity (ADCC)
...
These tagged cells are then recognised by
natural killer (NK) cells and macrophages (recognised via IgG bound (via the Fc
region) to the effector cell surface receptor, CD16 (FcγRIII)), which in turn kill
these tagged cells
...
These include:
 Pemphigus: IgG antibodies that react with the intracellular substance found
between epidermal cells
...
Also Rh antigen on RBCs
can elicit this condition
...

It is characterized by soluble antigens that are not bound to cell surfaces
...
Large
complexes can be cleared by macrophages but they have difficulty binding to
small immune complexes for clearance
...
Thjs
tissue deposition may lead to reaction with complement inducing an inflammatory
response causing tissue damage wherever they precipitate
...


One example of Type III hypersensitivity is serum sickness, a condition that
may develop when a patient is injected with a large amount of e
...
antitoxin that
was produced in an animal
...

Type IV hypersensitivity
Type IV hypersensitivity is often called delayed type hypersensitivity as the
reaction takes two to three days to develop
...

This type of hypersensitive (allegic) reaction occurs when an antigen interacts
with antigen-specific lymphocytes that release inflammatory and toxic
substances, which attract other white blood cells and results in tissue injury
...
Macrophages
function as antigen-presenting cells and release interleukin-1, which promotes
the proliferation of helper T-cells
...

Examples of Type IV reaction:
Contact Hypersensitivity is characterized by a reaction at the site of contact
with the allergen (like contact dermatitis)
...
The cell involved in antigen
presentation at this site is the Langerhans cell
...
A variety of cytokines are
involved in this process, including IL-2, IL-3, IFN and Granulocyte macrophage

colony-stimulating factor (GM-CSF)
...

Tuberculin Hypersensitivity
...
In these individuals fever, general unwellness, plus an area of
red, hard swelling was observed
...

This reaction is induced by a series of cellular migrations and activations:
 T-cell migration from capillaries
...

 Macrophage infiltration
...

In humans, these genes are referred to as human leukocyte antigen (HLA)
genes
...
Class I molecules are found on all nucleated cells (not red blood cells)
whereas class II molecules are found only on antigen presenting cells, (APCs)
which include dendritic cells, macrophages, B cells and a few other types
...
g
...




The class I and II MHC genes encode human leukocyte antigens (HLAs),
proteins that are displayed on the cell surface and define an individual’s
tissue type
...
This is why the body rejects grafts and transplants from donors
that have not been matched for tissue type
...

The class I and II MHC proteins also perform the important function of antigen
presentation
...
This helps the

immune system to spare normal (self) antigens and mount desired immune
response against foreign and potentially dangerous antigens
...

a long α chain and
II
...

The α chain has four regions
...

 A transmembrane region containing hydrophic amino acids by which the
molecule is anchored in the cell membrane
...

 A highly polymorphic peptide binding region (groove) formed from the α1 and
α2 domains
...
For every class I molecule, there are certain amino acids
that must be a particular location in the peptide before it will bind to the MHC
molecule
...


Structure of Class II MHC Molecules
Class II MHC molecules are composed of two polypeptide chains an α and a β
chain of approximately equal length (Figure above)
...


The groove of Class II molecules is open at one end so that the groove can
accommodate longer peptides of approximately 13-25 amino acids long with
some of the amino acids located outside of the groove
...
Because class II molecules are polymorphic, different
class II molecules can bind different peptides
...

MHC are highly polymorphic
There are 6 genes that encode MHC class I molecules HLA-A, HLA –B, HLA-C,
HLA-E, HLA-F and HLA-G
...

Polymorphism of class I MHC genes
Locus

Number of alleles
(allotypes)

HLA-A

218

HLA-B

439

HLA-C

96

HLA-E, HLA-F and
HLA-G

Relatively few alleles

There are 5 loci that encode class II molecules, each of which contains a gene
for an α chain and at least one gene for a β chain
...
Among these, HLA-DP,
HLA-DQ, and HLA-DR are the most important and are most polymorphic
...

There are four principal types: A, B, AB, and O
...
The specific
combination of these four components determines an individual's type in most
cases
...


ABO
Blood Type

A
B
O
AB

Antigen Antigen
Antibody Antibody
A
B
anti-A
Anti-B
yes
no
no
yes

no
yes
no
yes

no
yes
yes
no

Yes
No
Yes
No

For example, people with type A blood will have the A antigen on the surface of
their red cells (as shown in the table below)
...
However, if B type blood is injected into their systems, anti-B antibodies in
their plasma will recognize it as alien and burst or agglutinate the introduced red
blood cells in order to cleanse the blood of alien protein
...
Therefore, their
blood normally will not be rejected when it is given to others with different ABO
types
...
Those who have type AB blood do
not make any ABO antibodies
...
Consequently, they are universal receivers for transfusions, but
their blood will be agglutinated when given to people with every other type
because they produce both kinds of antigens
...

1
...
If blood cells stick together, it means the blood reacted with one of
the antibodies
...


2
...
Persons with Type A blood have anti-B antibodies, and those with
Type B blood have anti-A antibodies
...
These two steps can accurately determine your blood type
...

If your blood clumps together when A cells are added to your sample, you
have type B blood
...

Lack of blood cells sticking together when your sample is mixed with both
types of blood indicates you have type AB blood
...
Your blood serum has antibodies that
fight against type B blood
...
Your plasma has antibodies that fight
against type A blood
...
Your plasma has
antibodies that fight against both type A and type B blood
...
Your plasma does not
have antibodies against type A or type B blood
...
If you have this substance, you are
considered Rh+ (positive)
...
Rh
typing uses a method similar to ABO typing
...

If your blood does not clot when mixed with anti-Rh serum, you have type Rhnegative blood

Why and When are Blood type tests done?


Before a person gets a blood transfusion, donates blood or organ for
transplant and before surgery
...
If you get a transfusion that has
different antigens (incompatible blood), the antibodies in your plasma will
destroy the donor blood cells
...



When a woman is planning to become pregnant or first becomes pregnant
...
A problem can
occur when a woman who has Rh-negative blood becomes pregnant with a
baby (fetus) that has Rh-positive blood
...
If the
blood of an Rh-positive baby mixes with the blood of an Rh-negative mother
during pregnancy or delivery, the mother's immune system makes antibodies
...

Rh sensitization does not generally affect the health of the baby during the
pregnancy in which the sensitization occurs
...
After
sensitization has occurred, the baby can develop mild to severe problems
(called Rh disease or erythroblastosis fetalis)
...

The Rh test is done in early pregnancy to check a woman's blood type
...





To show whether two people could be blood relatives
...

In other words, the body actually attacks its own cells
...
Any disease that
results from such an aberrant immune response is termed an autoimmune
disease
...

Low-level autoimmunity

While a high level of autoimmunity is unhealthy, a low level of autoimmunity may
actually be beneficial
...
Neoplasia is the abnormal proliferation of cells
...

Second, autoimmunity may have a role in allowing a rapid immune response in
the early stages of an infection when the availability of foreign antigens limits the
response (i
...
, when there are few pathogens present)
...
This breakage leads to the immune system's mounting an
effective and specific immune response against self determinants
...
For their work Frank M
...
Medawar were
awarded the 1960 Nobel Prize in Physiology or Medicine "for discovery of
acquired immunological tolerance"
...




Idiotype Network theory, proposed by Jerne, wherein a network of
antibodies capable of neutralizing self-reactive antibodies exists naturally
within the body
...



The "Suppressor population" or "Regulatory T cell" theories, wherein
regulatory T-lymphocytes (commonly CD4+FoxP3+ cells, among others)
function to prevent, downregulate, or limit autoaggressive immune responses
...
This susceptibility is associated with multiple genes plus other risk
factors
...

Three main sets of genes are suspected in many autoimmune diseases
...


The first two, which are involved in the recognition of antigens, are inherently
variable and susceptible to recombination
...

Scientists have also provided strong evidence to suggest that certain MHC class
II allotypes are strongly correlated with some autoimmune disorders:


HLA DR2 is strongly positively correlated with Systemic Lupus
Erythematosus, narcolepsy and multiple sclerosis, and negatively correlated
with DM Type 1
...




HLA DR4 is correlated with the genesis of rheumatoid arthritis, Type 1
diabetes mellitus, and pemphigus vulgaris
...

Nearly 75% of the more than 23
...

The reasons for the sex role in autoimmunity are unclear
...
Involvement of sex
steroids is indicated by that many autoimmune diseases tend to fluctuate in
accordance with hormonal changes, for example, during pregnancy, in the
menstrual cycle or when using oral contraception
...
It has been
suggested that the slight exchange of cells between mothers and their children
during pregnancy may induce autoimmunity
...

Another theory suggests the female high tendency to get autoimmunity is due to
an imbalanced X chromosome inactivation
...

Environmental Factors
In areas where multiple infectious diseases are endemic, autoimmune diseases
are quite rarely seen
...
The
hygiene hypothesis attributes these correlations to the immune manipulating
strategies of pathogens
...
This may provide a serendipitous benefit to a
host that also suffers from autoimmune disease
...

Certain chemical agents and drugs can also be associated with the genesis of
autoimmune conditions, or conditions that simulate autoimmune diseases
...
This may relate to abnormal citrullination of
proteins, since the effects of smoking correlate with the presence of antibodies to
citrullinated peptides
...
Some of the mechanism summaries are described
below:


T-Cell Bypass - A normal immune system requires the activation of B-cells
by T-cells before the former can produce antibodies in large quantities
...




T-Cell-B-Cell discordance - A normal immune response is assumed to
involve B and T cell responses to the same antigen, even if we know that B
cells and T cells recognise very different things: conformations on the surface
of a molecule for B cells and pre-processed peptide fragments of proteins for
T cells
...
All that
is required is that a B cell recognising antigen X endocytoses and processes
a protein Y (normally =X) and presents it to a T cell
...
In coeliac disease it seems likely that B cells
recognising tissue transglutamine are helped by T cells recognising gliadin
...

These ligands include B cell receptor (for antigen), IgG Fc receptors, CD21,
which binds complement C3d, Toll-like receptors 9 and 7 (which can bind
DNA and nucleoproteins)
...
The idea of molecular mimicry arose in the
context of Rheumatic Fever, which follows infection with Group A betahaemolytic streptococci
...
Moreover, the complex tissue
distribution of the disease (heart, joint, skin, basal ganglia) argues against a
cardiac specific antigen
...
g
...




Idiotype Cross-Reaction - Idiotypes are antigenic epitopes found in the
antigen-binding portion (Fab) of the immunoglobulin molecule
...
In this case, the host-cell receptor is envisioned as an internal
image of the virus, and the anti-idiotype antibodies can react with the host
cells
...
The second category of cytokines, which
include IL-4, IL-10 and TGF-β (to name a few), seem to have a role in
prevention of exaggeration of pro-inflammatory immune responses
...
Dendritic cells that are defective in apoptosis
can lead to inappropriate systemic lymphocyte activation and consequent
decline in self-tolerance
...
In contrast
to molecular mimicry, the other epitopes need not be structurally similar to the
primary one
...

those that damage many organs (systemic autoimmune diseases) and
ii
...

However, the distinctions become blurred as the effect of localized autoimmune
disorders frequently extends beyond the targeted tissues, indirectly affecting
other body organs and systems
...
It usually affects multiple
joints symmetrically, the hand and wrists most commonly, but also elbows, neck,
shoulders, hips, knees, and feet
...


Normal and arthritis joints

Hands affected by RA
Patients with RA may develop anemia, systemic complications, and may have
other co-existing autoimmune disorders and symptoms such as the dry eyes and
mouth associated with Sjögren’s syndrome
...
More than 75% of those affected are women
...

RA is different from osteoarthritis, in which joint tissue wears down from sports or
injuries
...
The disease may be partly inherited through genes,
but other factors are probably at work, including some kind of a trigger for the
gene, perhaps bacteria or viruses
...

Some scientists also think that changes in certain hormones may promote RA in
people with certain genes who have been exposed to the triggering agent
...

JRA is a chronic condition that causes joint inflammation, pain, swelling, redness,

and stiffness
...
About one-fifth of
those with JRA have an enlarged spleen as well as joint inflammation
...
These types are:
Pauciarticular – about 50% of the cases of JRA are of this type
...

Polyarticular – about 30% of those with JRA have this type
...

Systemic – about 20% of those with JRA are of this type
...
Children with this type may have frequent fevers and rashes
that can come and go rapidly
...
It may also cause
uneven growth in the joint itself
...

The cause of JRA is unknown, but it is thought to be an autoimmune disorder
...
It usually begins between the ages of 2 and 5
years or between 9 and 12 years
...

Lupus
Lupus is a chronic, inflammatory autoimmune disorder that may affect the skin,
joints, blood cells, and internal organs, especially the kidneys, heart and lungs
...
Of these, systemic lupus erythematosus (SLE) is the most
common and serious form of lupus
...
There is an increased incidence of lupus in persons of
African, Asian, Hispanic, and Native American descent
...
It is thought to involve both an inherited component and a
trigger that may be related to environmental factors and/or to hormones
...

Symptoms and signs of lupus are highly variable and include: muscle pain;
arthritis-like pain in one or more joints (but no or little joint damage); a red rash –
particularly one resembling a butterfly across the nose and cheeks; fever,
persistent fatigue; sensitivity to ultraviolet light; and hair loss
...
Kidney
disease is a frequent occurrence in patients with lupus
...
Damage to other organs and tissues can lead to
complications including seizures, depression, psychoses or headaches, blood
clots leading to strokes, and pulmonary embolisms (blood clot in the lung)
...

They may worsen abruptly with flare-ups and then die back down
...
Pregnant women may
experience flare-ups during pregnancy or shortly after giving birth and may also
have miscarriages
...
There are, however, a number of
environmental triggers and a number of genetic susceptibilities
...
Research indicates that SLE may
have a genetic link
...
Instead, multiple genes appear to influence a person's chance of
developing lupus when triggered by environmental factors
...
HLA class I, class II, and class III
are associated with SLE, but only class I and class II contribute independently to
increased risk of SLE
...
They include certain medications (such as some antidepressants
and antibiotics), extreme stress, exposure to sunlight, hormones, and infections
...
Sex hormones such as estrogen
play an important role in the occurrence of SLE and it is observed that during
reproductive years, the frequency of SLE is 10 times greater in females than in
males
...
Drug-induced lupus
mimics SLE
...
There are about 400

medications that can cause this condition, the most common of which are
procainamide, hydralazine, quinidine, and phenytoin
...
Several techniques are
used to detect ANAs
...
The pattern of fluorescence suggests the type of antibody
present in the patient's serum
...
Subtypes of
antinuclear antibodies include anti-Smith and anti-double stranded DNA (dsDNA)
antibodies (which are linked to SLE) and anti-histone antibodies (which are linked
to drug-induced lupus)
...
5% of people without
SLE
...

Treatment
The treatment of SLE involves preventing flares and reducing their severity and
duration when they occur
...
Certain types of
lupus nephritis such as diffuse proliferative glomerulonephritis require bouts of
cytotoxic drugs
...

Sjögren’s syndrome
Sjögren’s syndrome is an autoimmune disorder in which the body’s immune
system mistakenly reacts to the tissue in the exocrine glands that produce
moisture such as tear and salivary glands
...
It is
characterized by unusual infiltration of these glands that are responsible for fluid
production by lymphocytes, thus causing decreased saliva (dry mouth),
decreased tear production (dry eyes), and drying of other mucous membranes
...

Sjögren’s syndrome can affect anyone at any age, but about 90% of those
affected are women, the majority of whom are older than 40, although Sjögren's
occurs in all age groups in both women and men
...
Sjögren's syndrome can exist as a
disorder in its own right (Primary Sjögren's syndrome) or it may develop years
after the onset of an associated rheumatic disorder such as rheumatoid arthritis,
systemic lupus erythematosus, scleroderma, primary biliary cirrhosis etc
...
In addition, Sjögren's syndrome may cause skin,
nose, and vaginal dryness, and may affect other organs of the body, including
the kidneys, blood vessels, lungs, liver, pancreas, peripheral nervous system
(distal axonal sensorimotor neuropathy) and brain
...
Patients with
secondary Sjögren's syndrome also have signs and symptoms associated with
rheumatic disorder
...

Diagnosis
Diagnosing Sjögren's syndrome is complicated by the range of symptoms a
patient may manifest, and the similarity between symptoms from Sjögren's
syndrome and those caused by other conditions
...



Blood tests can be done to determine if a patient has high levels of antibodies
that are indicative of the condition, such as anti-nuclear antibody (ANA) and
rheumatoid factor (because SS frequently occurs secondary to rheumatoid
arthritis), which are associated with autoimmune diseases
...




The Schirmer test measures the production of tears: a strip of filter paper is
held inside the lower eyelid for five minutes, and its wetness is then measured
with a ruler
...
However, lacrimal function declines with age or may
be impaired from other medical conditions
...
Salivary gland function can be
tested by collecting saliva and determining the amount produced in a five
minute period
...




Ultrasound examination of the salivary glands is the simplest confirmatory test
and has the added advantage of being non-invasive with no complications
...

Often sialectasis with calculi are demonstrated if the disease is advanced
...
The other
advantage of ultrasound is that complications of the disease such as extranodal lymphomas can often be detected as larger 1–4 cm hypoechoic intraparenchymal masses
...
A contrast agent is injected into the parotid
duct (of Stensen), which is a duct opening from the cheek into the vestibule of
the mouth opposite the neck of the upper second molar tooth
...


Treatment
There is neither a known cure for Sjögren's syndrome nor a specific treatment to
permanently restore gland secretion
...
Moisture replacement therapies such as artificial tears may ease
the symptoms of dry eyes (some patients with more severe problems use
goggles to increase local humidity or have punctal plugs inserted to help retain
tears on the ocular surface for a longer time)
...
Prescription drugs are also available
that help to stimulate salivary flow, such as cevimeline (Evoxac) and pilocarpine
...
For individuals with severe complications, corticosteroids or
immunosuppressive drugs may be prescribed
...

Hydroxychloroquine (Plaquenil) is another option and is generally considered
safer than methotrexate
...

Symptoms of polymyalgia rheumatica usually begin quickly over a few days
...

Most PMR sufferers wake up in the morning with pain in their muscles; however,
there have been cases in which the patient has developed the pain during the
evenings
...
PMR
usually goes away within a year or two after treatment

Symptoms and signs
There is a wide range of symptoms that indicate if a person has polymyalgia
rheumatica
...
Fatigue and lack of
appetite (possibly leading to weight loss) are also indicative of polymyalgia
rheumatica
...
Recent
studies have found that inherited factors also play a role in the probability that an
individual will become sick with polymyalgia rheumatica
...
Several viruses are thought to be linked to polymyalgia rheumatica,
including the adenovirus, which causes respiratory infections; the human
parvovirus B19, an infection that affects children; and the human parainfluenza
virus
...
There are many
other diseases which cause inflammation and pain in muscles, but there are a
few tests that can help narrow down the cause of the pain
...
This is confirmed by the test below
...
It
measures how fast the patient's red blood cells settle in a test tube
...
Many conditions can cause an elevated ESR, so this test alone is
not proof that a person has polymyalgia rheumatica
...
CRP is produced by the liver in response to an injury or
infection and people with polymyalgia rheumatica usually have high levels
...

Guillain-Barre Syndrome (GBS)
Guillain-Barre Syndrome (GBS) is an acute condition that involves progressive
muscle weakness or paralysis
...
This damage (called
demyelinazation) slows or stops the conduction of impulses through the nerve
...
Affected patients may become so weak
that they have trouble breathing and their heart rate becomes abnormal
...
It is
caused by an auto-immune response directed against Schwann cell membranes
...
It usually affects the eye muscles first and presents with the triad of
ophthalmoplegia, ataxia, and areflexia
...

Acute motor axonal neuropathy (AMAN), also termed as Chinese Paralytic
Syndrome, attacks motor nodes of Ranvier and is prevalent in China and Mexico
...
The disease may be seasonal and recovery can be rapid
...
Anti-GD3 antibodies are found more
frequently in AMAN
...
Like AMAN, it is likely
due to an auto-immune response directed against the axoplasm of peripheral
nerves
...

Acute panautonomic neuropathy is the most rare variant of GBS, sometimes
accompanied by encephalopathy
...
Impaired sweating,
lack of tear formation, photophobia, dryness of nasal and oral mucosa, itching
and peeling of skin, nausea, dysphagia, constipation unrelieved by laxatives or
alternating with diarrhea occur frequently in this patient group
...
The most
common symptoms at onset are related to orthostatic intolerance, as well as
gastrointestinal and sudomotor dysfunction
...

Bickerstaff’s brainstem encephalitis (BBE) is a further variant of Guillain–
Barré syndrome
...
The course
of the disease can be monophasic or remitting-relapsing
...
BBE despite severe initial presentation usually has a good
prognosis
...
The targets of such immune attack are thought to be gangliosides,
compounds naturally present in large quantities in human nerve tissues
...

However, 60% of cases do not have a known cause; one study suggests that
some cases are triggered by the influenza virus, or by an immune reaction to the
influenza virus
...

Cerebrospinal fluid analysis (through a lumbar spinal puncture) and
electrodiagnostic tests of nerves and muscles (such as nerve conduction studies)
are common tests ordered in the diagnosis of GBS
...
As opposed to
infectious causes, this is an elevated protein level (100–1000 mg/dL), without an
accompanying increased cell count pleocytosis
...

 Electrodiagnostics
Electromyography (EMG) and nerve conduction study (NCS) may show
prolonged distal latencies, conduction slowing, conduction block, and temporal
dispersion of compound action potential in demyelinating cases
...

Treatment:
Either high-dose intravenous immunoglobulins (IVIg) at 400 mg/kg for 5 days or
plasmapheresis can be administered as they are equally effective and a
combination of the two is not significantly better than either alone
...
IVIg is usually used first because of its
ease of administration and safety profile, with a total of five daily infusions for a
total dose of 2 g/kg body weight (400 mg/kg each day)
...
If plasmapheresis is chosen,

a dose of 40-50 mL/kg plasma exchange (PE) can be administered four times
over a week
...
)
 Addison's disease (adrenal)
 Primary biliary cirrhosis, Sclerosing cholangitis, Autoimmune hepatitis (liver)
 Temporal Arteritis / Giant Cell Arteritis (arteries of the head and neck)
1
...
It usually begins in childhood or young adulthood before the age of 25,
but can develop at any age
...

Causes of Type 1 Diabetes Mellitus
Genetic susceptibility:
 A family history of Type 1 Diabetes mellitus is often found
...

 Majority of the cases of Type 1 diabetes has been seen in individuals with
HLA-D phenotypes (HLA-DR3 and HLA-DR4)
...
Thereby leading to raised glucose level and thus diabetes mellitus
...
e
...

 Type 1 Diabetes may also be associated with other autoimmune diseases
such as Hashimoto’s thyroiditis
...

 Exposure to cow’s milk rather than maternal milk in infancy may lead to
development of type 1 DM
...

 Geography also plays an important role, as the incidences of Type 1 DM are
mainly high in Finland and Sardinia

Whatever the cause, once the islet cells are destroyed, you'll produce little or no
insulin, a hormone needed to allow sugar (glucose) to enter cells to provide
energy to your muscles and tissues
...


Signs and symptoms include:


Increased thirst and frequent urination
...
This may leave you thirsty
...




Extreme hunger
...
This triggers intense hunger
that may persist even after you eat
...




Weight loss
...
Without the energy sugar supplies, your muscle
tissues and fat stores may simply shrink
...
If your cells are deprived of sugar, you may become tired and
irritable
...
If your blood sugar level is too high, fluid may be pulled from
your tissues including the lenses of your eyes
...


Diagnosis
The diagnosis of diabetes is based on the symptoms and blood tests
...
Having a higher than normal
blood sugar, as well as the symptoms described above, usually means that you
have diabetes
Treatment/Management
Despite active research, type 1 diabetes has no cure and the only
treatment/management for type 1 diabetes is a lifelong commitment to:





Taking insulin
Exercising regularly and maintaining a healthy weight
Eating healthy foods
Monitoring blood sugar

The goal is to keep the blood sugar level as close to normal as possible to delay
or prevent complications
...
Hashimoto's thyroiditis
Hashimoto's thyroiditis is a condition caused by inflammation of the thyroid gland
...

The cause of the autoimmune process is unknown
...
Hashimoto's thyroiditis is
5-10 times more common in women than in men and most often starts in
adulthood
...
As result of the antibodies' interaction with the
enzyme, inflammation develops in the thyroid gland, the thyroid gland is
destroyed, and the patient ultimately is rendered hypothyroid (too little thyroid
hormone)
...

Hashimoto's thyroiditis diagnosis
Diagnosing Hashimoto's thyroiditis requires assessement of the symptoms, the
neck examinination, and detailed history of family members
...
The blood tests look at the thyroid function in
general
...
When hypothyroidism is present, the blood levels of
thyroid hormones can be measured directly and are usually decreased
...
However, thyroid hormone
medication can replace the hormones the thyroid made before the inflammation
started
...
Replacing one or both of these hormones can alleviate the symptoms
caused by the absolute or relative lack of hormones as a consequence of
Hashimoto's thyroiditis
...
Celiac disease
Celiac disease is a digestive condition triggered by consumption of the protein
gluten, which is found in bread, pasta, cookies, pizza crust and many other foods
containing wheat, barley
...

Eventually, the decreased absorption of nutrients (malabsorption) that occurs
with celiac disease can cause vitamin deficiencies that deprive your brain,
peripheral nervous system, bones, liver and other organs of vital nourishment
...
Thus,
approximately 10% of first-degree relatives (parents, siblings or children) of
individuals with celiac disease also will have celiac disease
...

Signs and symptoms:
There are two categories of signs and symptoms:
 Signs and symptoms due to malabsorption, which include diarrhoea,
malodorous flatulence (foul smelling gas), abdominal bloating, and increased
amounts of fat in the stool
...

Treatment
There is no cure for celiac disease
...

4
...
It affects all age groups and afflicts men and
women equally
...
The
problem may be due to a disorder of the adrenal glands themselves (primary
adrenal insufficiency) or to inadequate secretion of ACTH by the pituitary gland
(secondary adrenal insufficiency)
...
The
immune system makes antibodies that attack the body's own tissues or organs
and slowly destroy them
...
As a result, often both glucocorticoid (cortisol) and
mineralocorticoid (aldosterone) hormones are lacking
...
Cortisol can be replaced orally with
hydrocortisone tablets, a synthetic glucocorticoid
...


IMMUNODEFICIENCIES
Introduction
Disruption of any part of the orchestrated immune response can result in an
inability to control infection and subsequent illness
...
Complement proteins are an
important class of soluble mediators of the innate immune response and serve to
promote inflammation and microbial killing of extra-cellular pathogens
...
The cellular immune response is mediated
primarily by T cells and limits intracellular infections by organisms such as
viruses, parasites, and mycobacteria
...
T-lymphocyte and B-lymphocyte responses are not
independent of one another; for example, B cells can activate antigen-specific T
cells for a cellular immune response, while an efficient B-cell antibody response
depends in part on T-cell activation of B lymphocytes
...


Categories of Immunodeficiency
 Primary immunodeficiency
 Acquired immunodeficiency or secondary immunodeficiency
Primary immunodeficiency (PID)
Primary immunodeficiencies are disorders in which part of the body's immune
system is missing or does not function properly
...
e
...
Most primary immunodeficiencies are genetic disorders; the majority
are diagnosed in children under the age of one, although milder forms may not
be recognised until adulthood
...

The treatment of primary immunodeficiencies depends on the nature of the
defect, and may involve
a
...
long-term antibiotics and (in some cases)
c
...

Primary immunodeficiency disorders:
1
...
T-cell defects and combined B-cell and T-cell defects
3
...
Complement deficiencies
Disorders of humoral immunity
Disorders of humoral immunity affect B-cell differentiation and antibody
production
...

Patients with antibody deficiencies often present after six months of age, when
maternal antibodies are lost, but they can present in adulthood
...
Recurrent bacterial
sinus and pulmonary infections are the hallmark of antibody primary
immunodeficiencies
...

Common variable immunodeficiency is the primary immunodeficiency
...
05 g per L])
...
10 Patients with common variable

immunodeficiency have a poor response to vaccines (decreased IgG antibody
response) and an increased risk of developing auto-immune disorders and
malignancy
...
Patients with symptoms often have sinusitis and respiratory tract
infections, along with gastrointestinal involvement
...
Although serum IgA
levels are below 5 mg per dL, serum IgG and IgM levels are in the normal range
...

Bruton's or X-linked agammaglobulinemia is caused by mutation or absence of
the Bruton's tyrosine kinase gene
...

Onset of recurrent bacterial infections is usually at the end of the first year of life;
however, patients with the disorder may not present until the age of three to five
years
...
These primary immunodeficiency disorders are
generally more severe than antibody deficiencies
...

DiGeorge syndrome also called (Thymic aplasia) is one of the most recognized
disorders in this category, and severe combined immunodeficiency is the most
severe
...



DiGeorge syndrome is caused by genetic defects of the thymus and often
the parathyroid glands and heart, associated with T-cell dysfunction and
significant immune deficiency
...
Associated defects include truncal cardiac
malformations (e
...
, truncus arteriosis, Fallot's tetralogy) and dysmorphic
facial features
...
5 × 109 per L]) and hypocalcemia of greater than
three weeks' duration
...
This disorder is characterized by severe opportunistic infections, or
by chronic diarrhea and failure to thrive in infancy
...
About one half of cases are X-

linked, and one half are autosomal recessive
...



Wiskott-Aldrich syndrome is an X-linked recessive syndrome characterized
by thrombocytopenia, small platelets and platelet dysfunction, eczema, and
susceptibility to infections
...
Patients
with this primary immunodeficiency disorder are at risk for autoimmune
diseases and cancer
...
Patients with this disorder have
difficulty walking and generally are wheelchair-bound by the teenage years
...
In this
disease, deficiency of nicotinamide adenine dinucleotide phosphate oxidase in
phagocytes results in defective elimination of extracellular pathogens such as
bacteria and fungi
...
g
...
Aspergillus infection is the most
common cause of death in patients with phagocytic primary immunodeficiency
disorders
...
They result from the disruption of one of the
proteins involved in the classic or nonclassic activation pathways of the
complement response
...
Patients with defects
of the alternative pathway characteristically present with Neisseria infection
...
This may range from immunoglobulin replacement therapy
intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) in
antibody deficiencies to hematopoietic stem cell transplantation (for SCID and
other severe immunodeficiences)
...

Acquired immunodeficiency (secondary immunodeficiency)
Immune deficiency may also be the result of particular external processes or
diseases; the resultant state is called "secondary" or "acquired"
immunodeficiency (i
...

Common causes for secondary immunodeficiency are malnutrition, aging and
particular medications (e
...
chemotherapy, disease-modifying antirheumatic
drugs, immunosuppressive drugs after organ transplants, glucocorticoids)
...
This
includes many types of cancer, particularly those of the bone marrow and blood
cells (leukemia, lymphoma, multiple myeloma), and certain chronic infections
...
HIV directly infects
a small number of T helper cells, and also impairs other immune system
responses indirectly
...
Other than
HIV and TB, secondary immunodeficiency is also common in people who are
hospitalised for various diseases:









Lymphoreticular malignancy: chronic lymphatic leukaemia and myeloma are
both associated with hypogammaglobulinaemia
...

Drugs: these particularly include cytotoxic drugs and immunosuppressants
including steroids
...
Other viral diseases, such as congenital rubella
infection and cytomegalovirus, can affect antibody production
...

Metabolic: prolonged metabolic disorders associated with liver and kidney
failure compromise immunity (this occurs in 10% of patients on continuous
ambulatory peritoneal dialysis)
...

Protein Loss: loss of immunoglobulin can result from a number of conditions
including nephrotic syndrome, protein-losing enteropathy and intestinal
lymphangiectasia
...
This
discriminatory ability provides protection from infectious disease, since most
microbes are identified as foreign by the immune system
...
Immunity is
generally very specific to a single organism or group of closely related
organisms
...
Passive immunity often
provides effective protection, but this protection wanes (disappears) with time,
usually within a few weeks or months
...
It provides protection against some infections, but this
protection is temporary
...


The most common form of passive immunity is that which an infant receives from
its mother
...
As a result, a full-term infant will have the same antibodies
as its mother
...
Protection is better against some diseases (e
...
, measles, rubella,
tetanus) than others (e
...
, polio, pertussis)
...

Homologous pooled human antibody also known as immune globulin is produced
by combining (pooling) the IgG antibody fraction from thousands of adult donors
Because it comes from many different donors, it contains antibody to many
different antigens
...

Homologous human hyperimmune globulins are antibody products that contain
high titers of specific antibody
...
However, since
hyperimmune globulins are from humans, they also contain other antibodies in
lesser quantities
...

Heterologous hyperimmune serum (also known as antitoxin)
...
In the United States, antitoxin is available for treatment of
botulism and diphtheria
...

Active Immunity
Active immunity is protection that is produced by the person’s own immune
system
...
It requires the stimulation of
the immune system to produce antigen-specific humoral (antibody) and cellular
immunity
...

One way to acquire active immunity is to have the natural disease
...
The persistence of protection for many years after the infection is
known as immunologic memory
...
Upon reexposure to the antigen,
these memory cells begin to replicate and produce antibody very rapidly to
reestablish protection
...
Vaccines interact with
the immune system and often produce an immune response similar to that
produced by the natural infection, but they do not subject the recipient to the
disease and its potential complications
...

Many factors may influence the immune response to vaccination
...
g
...

Host factors such as age, nutritional factors, genetics, and coexisting disease,
may also affect the response
...

Vaccines can be prophylactic (i
...
to prevent or ameliorate the effects of a future
infection by any natural or "wild" pathogen), or therapeutic (e
...
vaccines against
cancer still under investigation)
...

To date, there is no therapeutic vaccine that can cure a person having cancer
...
One approach to cancer vaccination is to separate proteins from
cancer cells and immunize cancer patients against those proteins, in the hope of
stimulating an immune reaction that would kill the cancer cells
...

Classification of Vaccines
There are two basic types of vaccines: live attenuated and inactivated
...

Live attenuated vaccines are produced by modifying a disease-producing (“wild”)
virus or bacterium in a laboratory
...

Inactivated vaccines can be composed of either wholeviruses or bacteria, or
fractions of either
...
Protein-based vaccines include toxoids (inactivated
bacterial toxin) and subunit or subvirion products
...
Conjugate
polysaccharide vaccines are those in which the polysaccharide is chemically
linked to a protein
...

 Live Attenuated Vaccines
Live vaccines are derived from “wild,” or disease-causing, viruses or bacteria
...
For example, the measles vaccine used today was
isolated from a child with measles disease in 1954
...

To produce an immune response, live attenuated vaccines must replicate (grow)
in the vaccinated person
...
Anything that either damages the live organism
in the vial (e
...
, heat, light) or interferes with replication of the organism in the
body(circulating antibody) can cause the vaccine to be ineffective
...
When a live attenuated
vaccine does cause “disease,” it is usually much milder than the natural disease
and is referred to as an adverse reaction
...
The immune system does not differentiate
between an infection with a weakened vaccine virus and an infection with a wild
virus
...
They may cause severe or fatal reactions as a result of
uncontrolled replication (growth) of the vaccine virus
...
g
...

A live attenuated vaccine virus could theoretically revert to its original pathogenic
(disease-causing) form
...

Active immunity from a live attenuated vaccine may not develop because of
interference from circulating antibody to the vaccine virus
...
g
...


Measles vaccine virus seems to be most sensitive to circulating antibody
...
Live attenuated vaccines are
fragile and can be damaged or destroyed by heat and light
...

Currently available live attenuated viral vaccines are measles, mumps, rubella,
vaccinia, varicella, zoster (which contains the same virus as varicella vaccine but
in much higher titer), yellow fever, rotavirus, influenza (intranasal), and oral polio
vaccine
...

 Inactivated Vaccines
These are vaccines which contain killed, but previously virulent, micro-organisms
that have been destroyed with chemicals or heat
...
Also referred as killed vaccines
In the case of fractional vaccines, the organism is further treated to purify only
those components (usually inactivated toxic compounds that cause illness rather
than the micro-organism) to be included in the vaccine (e
...
, the polysaccharide
capsule of pneumococcus)
...

Inactivated vaccines always require multiple doses
...
A
protective immune response develops after the second or third dose
...

Antibody titers against inactivated antigens diminish with time
...

Examples of whole-cell inactivated vaccines include inactivated whole viral
vaccines (polio, hepatitis A, rabies and influenza), whole inactivated bacterial
vaccines (pertussis, typhoid, cholera, and plague)
...
Not all toxoids are for
micro-organisms; for example, Crotalus atrox toxoid is used to vaccinate dogs
against rattlesnake bites
...

These products are sometimes referred to as recombinant vaccines
...

Examples of genetically engineered vaccines currently in use
...
The modified yeast cell produces pure hepatitis B surface antigen or
HPV major capsid protein when it grows
...
Live attenuated influenza vaccine
has been engineered to replicate effectively in the mucosa of the
nasopharynx but not in the lungs
...
Pure polysaccharide vaccines are available for three diseases:
pneumococcal disease, meningococcal disease, and Salmonella Typhi
...
”
Antibody induced with polysaccharide vaccines has less functional activity than
that induced by protein antigens
...

the problems noted above could be overcome through a process called
conjugation, in which the polysaccharide is chemically combined with a protein
molecule
...
g
...
The conjugation therefore changes the immune response
from T-cell independent to T-cell dependent, leading to increased
immunogenicity in infants and antibody booster response to multiple doses of
vaccine
...
Other conjugate vaccine e
...
for pneumococcal disease
and meningococcal diseases were licensed in 2000 and 2005 respectively
...
A monovalent vaccine is designed to immunize against a single
antigen or single microorganism
...


MONOCLONAL ANTIBODIES & HYBRIDOMA
TECHNOLOGY
Monoclonal antibodies (mAb) are monospecific antibodies that are the same
because they are made by one type of immune cell that are all clones of a unique
parent cell
...
Development of the hybridoma technology
has reduced the number of animals (mice, rabbits, and so on) required to
produce a given antibody
...
Intact cells, whole
membranes, and microorganisms are sometimes used as immunogens
...

Step 2: Screening of Mice for Antibody Production
After several weeks of immunization, blood samples are obtained from mice for
measurement of serum antibodies
...
If the antibody titer is high, cell fusion can be performed
...
When the antibody titer is high enough,
mice are commonly boosted by injecting antigen without adjuvant
intraperitoneally or intravenously (via the tail veins) 3 days before fusion but 2
weeks after the previous immunization
...


Schematic representation of general monoclonal antibodies production procedure

Flow chart representing general monoclonal antibodies production summary

Step 3: Preparation of Myeloma Cells
Fusing antibody-producing spleen cells, which have a limited life span, with cells
derived from an immortal tumor of lymphocytes (myeloma) results in a hybridoma
that is capable of unlimited growth
...
Cells must
have high viability and rapid growth
...
Fusion is accomplished by co-centrifuging freshly
harvested spleen cells and myeloma cells in 30 to 50% (w/v) polyethylene glycol
(a substance that causes cell membranes to fuse) for only a few minutes since
polyethylene is toxic to cells
...

Lymphocytes and fused lymphocytes soon die as they cannot be cultured in vitro
...
Hybridomas (fusion products of B lymphocytes and HPGRT
negative cells can survive because the myloma cells confers the ability to grow in
vitro and the B lymphocytes contribute the HPGRT essential for growth in the
HAT medium
...

By exposing cells to aminopterin (a folic acid analogue, which inhibits
dihydrofolate reductase, DHFR), they are unable to use the de novo nucleic acid
synthesis pathway
...

The cells are then distributed to 96 well plates containing feeder cells derived
from saline peritoneal washes of mice
...
Commercial
preparations that result from the collection of media supporting the growth of
cultured cells and contain growth factors are available that can be used instead
of mouse-derived feeder cells
...

However, most of these will be producing either unwanted immunoglobulin or no
immunoglobulin and unfortunately, non-immunoglobulin producing hybridomas
have a tendancy to outgrow the immunoglobulin producing ones
...
Useful
immunoglobulin producing cultures should be sub-cultured and aliquots stored at
-196°C to minimize contamination by microorganisms
...


Cloning
Clone: a family of cells of genetically identical constitution derived asexually from
a single cell by repeated division
There are two methods of cloning:


Cultures may be diluted to limiting dilution and distributed so that each well of
a microtitre plate contains only one hybridoma cell
...




Hybrids may be diluted and seeded into sloppy nutrient agar so that individual
clones may be observed growing and picked out with a Pasteur pipette
...


In both cases, tests such as ELISA or Antigen Microarray Assay) or immuno-dot
blot are used
...
The clone is aliquoted and stored at -196°C
...

 The cells can be injected in mice (in the peritoneal cavity, the gut), where they
produce tumors containing an antibody-rich fluid called ascites fluid
...




---